Recurring homozygous ACTN2 variant (p.Arg506Gly) causes a recessive myopathy.
Recurring homozygous ACTN2 variant (p.Arg506Gly) causes a recessive myopathy.
复制标题
复发性纯合 ACTN2 变异 (p.Arg506Gly) 会导致隐性肌病。
DOI：
10.1002/acn3.51983
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发表时间：
2024
影响因子：
5.3
通讯作者：
Cohen,
中科院分区：
文献类型：
--
作者：
Donkervoort,Sandra;Mohassel,Payam;O'Leary,Melanie;Bonner,DevonE;Hartley,Taila;Acquaye,Nicole;Brull,Astrid;Mozaffar,Tahseen;Saporta,MarioA;Dyment,DavidA;Sampson,JacindaB;Pajusalu,Sander;Austin-Tse,Christina;Hurth,Kyle;Cohen,
ACTN2编码α-辅肌动蛋白-2，对心脏和骨骼肌肌节功能至关重要。ACTN2变体是一种已知的心肌病的原因，但不涉及骨骼肌。最近，特定的显性单等位基因变异被报道为一种罕见的原因，核心肌病的可变临床发病，但病理机制仍有待阐明。复发性遗传性ACTN2-肌病的可能性也被提出在一个单一的series.MethodsWe提供了一系列患者的临床，影像学和组织学特征与一个新的biallelicACTN2 variant.ResultsWe报告7例患者从5个家庭与复发性双等位基因变异在ACTN2：c.1516A> G（p.Arg506Gly），均表现出一致的不对称、进行性、近端和远端下肢主要肌无力表型。所有患者均无心肌病或呼吸功能不全。值得注意的是，所有患者报告巴勒斯坦种族，提示可能的founderACTN2变异，这是通过两个家庭的单倍型分析证实。肌肉活检揭示了一个潜在的肌病过程与肌原纤维间结构的破坏，I型纤维优势和萎缩。下肢的MRI显示了一种明显的不对称肌肉受累模式，大腿的腘绳肌和内收肌以及小腿的胫前肌群和比目鱼肌选择性受累。使用体外剪接分析，我们表明，c.1516A> GACTN2不损害正常splicing.Interpretation这一系列进一步确立ACTN2作为一个肌肉疾病基因，现在也包括变异与隐性遗传模式，并扩大临床范围的放线菌病成人发病进行性肌肉疾病。
ObjectiveACTN2,encoding alpha‐actinin‐2, is essential for cardiac and skeletal muscle sarcomeric function.ACTN2variants are a known cause of cardiomyopathy without skeletal muscle involvement. Recently, specific dominant monoallelic variants were reported as a rare cause of core myopathy of variable clinical onset, although the pathomechanism remains to be elucidated. The possibility of a recessively inherited ACTN2‐myopathy has also been proposed in a single series.MethodsWe provide clinical, imaging, and histological characterization of a series of patients with a novel biallelicACTN2variant.ResultsWe report seven patients from five families with a recurring biallelic variant inACTN2: c.1516A>G (p.Arg506Gly), all manifesting with a consistent phenotype of asymmetric, progressive, proximal, and distal lower extremity predominant muscle weakness. None of the patients have cardiomyopathy or respiratory insufficiency. Notably, all patients report Palestinian ethnicity, suggesting a possible founderACTN2variant, which was confirmed through haplotype analysis in two families. Muscle biopsies reveal an underlying myopathic process with disruption of the intermyofibrillar architecture, Type I fiber predominance and atrophy. MRI of the lower extremities demonstrate a distinct pattern of asymmetric muscle involvement with selective involvement of the hamstrings and adductors in the thigh, and anterior tibial group and soleus in the lower leg. Using anin vitrosplicing assay, we show that c.1516A>GACTN2 does not impair normal splicing.InterpretationThis series further establishesACTN2as a muscle disease gene, now also including variants with a recessive inheritance mode, and expands the clinical spectrum of actinopathies to adult‐onset progressive muscle disease.